Digoxin is currently the most widely clinically used cardiac glycoside, and is used in many patients with cardiac disease. Many factors may contribute to the relative effectiveness of digoxin, and may modulate either myocardial content of digoxin or its inotropic effect. Accordingly, this research proposal is designed to further investigate the actions of digoxin under a variety of circumstances similar to those observed in heart disease. The experiments outlined in this proposal will observe the inotropic effects and myocardial content of digoxin in either isolated cat papillary muscles or intact dog hearts. Observations will be made on the ability of digoxin to exert an inotropic effect during alterations of tissue oxygen consumption, during electrolyte disturbances, in the presence of acid-base imbalances, during ischemia with or without accompanying heart failure, or during myocardial infarction. Many of the experiments in the intact dog heart model will employ a myocardial biopsy technique so that the time course of myocardial uptake of digoxin, both during control conditions and under the influence of various experimetal interventions, can be examined. In the ischemia studies, regional contractility of discrete areas of the myocardium will be recorded and correlated with regional myocardial digoxin content in the same areas. These studies will thus provide useful information about the inotropic effects of digoxin and the ability of the myocardium to bind digoxin. Since all studies outlined in this proposal will monitor not only the inotropic effect of digoxin but cardiac muscle content as well, circumstances can be identified in which disparities exist between content and inotropic effect. Further, in the intact dog studied serum digoxin levels will be measured and compared to myocardial digoxin levels in order to see if any of the experimental interventions alter serum:myocardium digoxin ratios. The current research proposal will be an in-depth investigation of the ability of the myocardium to respond to digoxin and to bind digoxin during conditions seen clinically in patients with varying forms of cardiac disease.